Endocannabinoids, abundant endogenous lipid molecules, have various neurological functions such as cognitive alteration and neuroprotection. The production of endocannabinoids occurs rapidly in neurons upon a rise in Ca2+ or an activation of G proteins. Once released into extracellular space, endocannabinoids bind to presynaptic cannabinoid receptors and suppress synaptic transmission. Due to rapid production and uptake of endocannabinoids, their action is temporally limited. In addition to this phasic action of endocannabinoid, neurons tonically release endocannabinoid. However, regulatory mechanisms for endocannabinoid tone are largely unknown. Since tonic endocannabinoid level has been implicated in lasting state of neural activity such as anxiety and neurodegeneration, it is possible that the endocannabinoid tone may be regulated by chronic alterations of neuronal activity. The proposed studies aim to track down the cellular and molecular targets of the activity-dependent modification of tonic endocannabinoid signaling. This project will further determine functional significance of endocannabinoid tone in synaptic homeostasis and neurodegenerative disease, both of which involve chronic shift in neuronal activity. Persistent inactivity may induce both synaptic homeostasis and a change in basal endocannabinoid level, but the relationship between the two is poorly understood and therefore is proposed to be investigated here. If endocannabinoid tone is reduced, e.g., by chronic inactivity, the outcome may not be always advantageous, given the various beneficial functions of endocannabinoids. For example, detrimental effects of endocannabinoid deficiency could be accentuated when neuroprotection mediated by endocannabinoids is on high demand. I propose to test for roles of diminished endocannabinoid tone when neuronal activity is reduced in Alzheimer's disease models. The outcome of these studies will provide new perspectives on the regulation of endocannabinoid tone and its roles in physiological and pathological settings.